Dealkylation of alpha, beta-bis-(p-alkoxyphenyl)-alpha, beta-disubstituted ethanes and p,p&#39; dialkoxy-alpha, beta disubstituted stilbenes



' DEALKYLATION Brs- (ii-neon.

PnENYm-ap-msmsnwmo ETHANEs AND p.12 STIL'BENES Joseph Corse,

DIALKOXY- ,p DISUBS TITUTED 1 Indianapolis, Ina, assignorl to Eli Lillyand Company, Indianapolis, I nd., a. corporation of Indiana No Drawing.Application December 26, 1941,

Serial No. 424,500

6 Claims.

This invention relates to the dealkylation of a,fi-bis- (p-alkoxyphenyl)-a,,8-disubstituted ethanes. and Di :-dialkOXY-11,}3-dlSl1bSllll3lll38dstilbenes.

Heretofore'in the dealkylation of a,fi-blS-(palkoxyphenyl)-a,c-disubstituted ethanes and p,p'- dialkoxy-a,p-disubstitutedstilbenes, it was neessary to employ expensive Grignards reagents or touse alcohol solutions under pressure. Both of these methods entailedconsiderable equipment and involved material expense.

In accordance with the method of dealkylation of this invention, thesetwo types of compounds, oz,fi-biS- (p-alkoxyphenyl) -a,B-disubstitutedethanes and p,p'-dialkoxy-a, 3-disubstituted stilbenes, are convertedrespectively to the corresponding 0:,fi-blS- (p-hydroxyphenyl)a,l5-dlSlll)- stituted ethanes and p,p'-dihydroxy-a. 9disubstitutedstilbenes efliciently and economically.

The method of this invention is as follows:

A quantity of an alkali hydroxide, such as sodium hydroxide, potassiumhydroxide, or lithium hydroxide, equal to at least two molecularequivalents of the composition to be treated is dissolved in a solventconsists of water-soluble glycols having less than and water solublepolyalkylene glycols having less than ten carbon atoms. Exe amples ofthe glycols and polyalkylene glycols are: ethylene glycol, diethyleneglycol, propylene glycol, dipropylene glycol, and triethylene glycol.The alkali hydroxide is dissolved in the glycol or polyalkylene glycolby heating and stirring, the temperature of the solution being graduallyraised to at least 190 C. To the solution is added one molecularequivalent of a composition represented by either of the followingformulas;

in which R is an alkyl radical having less than 5 carbon atoms, R1 is analkyl radical having less than 5 carbon atoms,

alkenyl radicals having less than 5 carbon atoms. R and R1 arepreferably the same and are desirably the methyl or ethyl radical. Thecomposition is heated with a solution of the alkali hydroxide in theglycol or polyalkylene glycol selected from the class which at atemperatureoi not less than 190 C. and preferably up to 235 C. forseveral hours. The completion of the reaction can be readily ascertainedby taking an aliquot portion of the reaction mixture and diluting thataliquot portion with. 10 volumes of water. A clear or almost clearsolution indicates the completion of 'the reaction. During this time thealkali metal salt of the desired cud-bis-(p-hydroxyphenyl)we-disubstituted ethane or the p,p-dihydroxy-, 3-disubstituted stilbeneis formed. These resulting alkali metal salts can be readily convertedto the desired a,fi-bis-(p-hydroxyphenyl) -oz,fi-dlSll'bstituted ethaneor p,p'-dihydroxy-a,fl-disubstituted stilbenes by hydrolysis with astrong or weak acid, such as a mineral acid, for example, hydrochloricor sulfuric acid; an organic acid, for example, acetic acid; or carbondioxide. Upon the addition of the acid the desired compoundprecipitates. The crude material may be recrystallized from a suitablesolvent, such as alcohol or benzene.

Typical examples of the method of this invention are as follows:

Example I.Demethylati0n of p,p'-dimethoxyp-diethyl stilbene.

Fifty grams of potassium hydroxide is dissolved by heating and stirringin cc. of diethylene glycol contained in a or almost clear solutionindicates the completion of the reaction. During this time the potassiumsalt of the desired p.13-dihydroxy-e,p-diethyl acid,p.p'+dihydroxy-a,fi-diethyl stilbene precipitates. is crude material maybe recrystallized from alcohol, benzene, or other suitable solvent andyields a white crystalline product melting in the range 167-169.5 C. Theproduct so obtained has the maximum physiological activity of transp,p'-dihydroxy-a,p-diethyl stilbene.

Example 2.-The demethylation of p,p'-dimethoxy-a.p-diethyl stilbene.

Instead oi employing diethylene glycol as i Example 1, 150 cc.dipropylene glycol is employed. The procedure outlined in Example 1 isfollowed exactly except for the substitution of the dipropylene glycolfor the diethylene glycol.

Example 3.-Demethylation of 0:,fl-b1S-(P- methoxyphenyl) -a,,8-diethylethane.

The procedure described in Example 1 is followed except that instead ofusing 150 cc. of diethylene glycol, 250 cc. of ethylene glycol is usedand 50 g. of ,5-bis-(p-methoxyphenyl)-a,pdiethyl ethane (M. P. 140-1-i1C.) is used instead of 50 g. of D,p'-dimethoxy-a,p-diethyl stilbene. Theresulting product, a,,B-bis-(p-hydroxyphenyl)-a,p-diethyl ethane, meltsat 185- 186 C.

Example 4.--Demethylation of p,p'-dimethoxya-methyl-p-ethyl stilbene.

The procedure described in Example 1 is followed except that instead ofemploying 50 g. of p,p'-dimethoxy-a,,9-diethyl stilbene, 50 g, of p,p'-dimethoxy-a-methyl-p-ethyl stilbene is used. The resulting product,p,p'-dlhydroxy a-methylp-ethyl stilbene, melts at 1'75-176 C.(uncorrected).

Example 5.--Demethylation of p,p'-dimethoxyocfi-dl-Ii-b'L'ltYl stilbene.

The procedure described in Example 1 is followed except that 50 g. ofp,p'-dimethoxv-a,pdi-n-butyl stilbene is used instead of 50 g. ofp,p-dimethoxy-u,fi-diethyl stilbene. The resultingp,p'-dihydroxy-a,p-di-n-butyl stilbene is an uncrystallizable oil.

Example 6.-Demethylation of p,p'-dimethoxy-a,s-diallyl stilbene.

The procedure described in Example 1 is followed except that 50 g. ofp,p'-dimethoxy-a,fldiallyl stilbene is used instead of 50 g. of p,p'-dimethoxy-a,fi-diethyl stilbene. The resultingp,p'-dihydroxy-a,fi-diallyl stilbene is a line solid.

What is claimed is:

1. The method of dealkylating a composition selected from the classwhich consists of ufi-blsnoncrystal- (p-alkoxy-phenyl)-a,p-dialky1ethanes and ppdlalkoxy-ap-dialkyl stilbenes, the alkoxygroups and the alkyl groups of said ethanes and said stilbenes havingless than 5 carbon atoms; said method comprising reacting at atemperature above C. said composition with a solution of an alkalihydroxide dissolved in a solvent selected from the class which consistsof water-soluble glycols having less than 5 carbon atoms andwater-soluble polyalkylene glycols having less than 10 carbon atoms.

2. The method of dealkylating a composition selected from the classwhich consists of a,fl-blS- (p-alkoxy-phenyl) -a,p -dialkylethanes andpmdialkoxy-a,p-dialkyl stilbenes, the alkoxy groups and alkyl groups ofsaid ethanes and said stilbenes having less than 5 carbon atoms; saidmethod comprising reacting at a temperature above 190 C. saidcomposition with a solution of an alkali hydroxide dissolved in asolvent selected from the class which consists of watersoluble gycolshaving less than 5 carbon atoms and water-soluble polyalkylene glycolshaving less than 10 carbon atoms and hydrolyzing the resulting salt.

3. The method of dealkylating a composition in accordance with claim 1,in which the alkali hydroxide is potassium hydroxide.

4. The method of dealkylating a composition.

in accordance with claim 1, in which the solvent is diethylene glycol.

5. The method of dealkylating a'p,p-dialkoxyu fi-diethyl stilbene whichcomprises reacting at a temperature above 190 C. said stilbene with asolution of an alkali hydroxide dissolved in a solvent selected from theclass which consists of water-soluble glycols having less than 5 carbonatoms and water-soluble polyalkylene glycols having less than 10 carbonatoms.

6. The method of demethylating p,p'-dimethoxy-ap-diethyl stilbene whichcomprises reacting at a. temperature above 190 C. said stilbene withpotassium hydroxide dissolved in diethylene glycol.

JOSEPH CORSE.

